Combined stem cell transplantation and targeted microstimulation to direct the fo

描述（由申请人提供）：本研究的目的是开发和测试一种方法，以指导损伤或变性后中枢神经系统的修复和再生。我们认为，通过创造一个再生环境以及指导神经元之间的内在可塑性，我们可以实现神经修复的新里程碑。如果成功，这种方法可以用于治疗患有中枢神经系统损伤的患者，如创伤性脑损伤，中风或脊髓损伤，以减轻神经系统疾病对个人和社会的负担。我们的研究采用了一种新的靶向电微刺激和干细胞疗法的组合，以引导绕过损伤的适当和功能性连接的形成。我们将在代表整个中枢神经系统损伤的不完全颈脊髓损伤的啮齿动物模型中测试我们的方法。已知在神经系统发育期间，干细胞产生未成熟的星形胶质细胞，其创造支持轴突引导和突触可塑性的环境。在这里，我们假设，神经可塑性和受损神经元的修复可以通过重建损伤部位周围星形胶质细胞的发育表型来促进。在第一种方法中，我们将从自体成体干细胞中获得未成熟的星形胶质细胞，并将其移植到脊髓病变附近，为可塑性和神经修复创造支持性环境。我们认为，单独提供环境支持的成功有限，因为它没有解决神经元生长的内在驱动力。在完整和受损的神经系统中，还需要同步和适当的神经活动来指导功能性突触连接的形成。在这里，我们将使用一种神经假体装置，将微刺激传递到损伤下方脊髓内的目标部位，与运动皮层中的功能相关活动同步。有针对性的微刺激将通过赫布可塑性机制加强适当的和功能性的连接。我们的方法不是试图在脊髓中进行长束再生，而是旨在通过绕过病变的备用通路促进间接连接的形成。将使用行为任务、电生理学和组织学方法测量恢复程度。这将确定同步的、有针对性的微刺激引导植入的干细胞在中枢神经系统损伤后形成适当的功能性连接的能力。我们认为，微刺激将与移植环境合作，对局部可塑性产生倍增效应。

DESCRIPTION (provided by applicant): The goal of this research is to develop and test a method to guide repair and regeneration of the central nervous system following injury or degeneration. We propose that by creating both a regenerative environment as well as directing intrinsic plasticity among neurons, we can achieve a new milestone in neural repair. If successful, this approach could be used to treat patients suffering from central nervous system damage such as traumatic brain injury, stroke, or spinal cord injury in order to reduce the burden of neurological disease on individuals and society. Our studies employ a novel combination of targeted electrical microstimulation and stem cell therapies to guide the formation of appropriate and functional connections bypassing an injury. We will test our approach in a rodent model of incomplete cervical spinal cord injury that is representative of insults throughout the central nervous system. It is known that during development of the nervous system, stem cells produce immature astrocytes that create an environment to support axon guidance and synaptic plasticity. Here, we hypothesize that neural plasticity and the repair of damaged neurons can be facilitated by re-creating the developmental phenotype of astrocytes surrounding an injury site. In a first of its kind approach, we will derive immature astrocytes from autologous adult stem cells and transplant them near a spinal cord lesion to create a supportive environment for plasticity and neural repair. We propose that providing environmental support alone has had limited success because it does not address the intrinsic drive of neurons to grow. Synchronous and appropriate neural activity is also needed to direct the formation of functional synaptic connections in the intact and injured nervous system. Here we will use a neuroprosthetic device to deliver microstimulation to targeted sites within the spinal cord below the injury that is synchronized with functionally related activity in the motor cortex. Targeted microstimulation will strengthen appropriate and functional connections via mechanisms of Hebbian plasticity. Rather than attempt long-tract regeneration in the spinal cord, our approach aims to promote the formation of indirect connections via spared pathways bypassing the lesion. The extent of recovery will be measured using behavioral tasks, and electrophysiological and histological methods. This will determine the ability of synchronous, targeted microstimulation to guide implanted stem cells in the formation of appropriate and functional connections following damage to the central nervous system. We contend that microstimulation will collaborate with the transplant environment to produce a multiplicative effect on local plasticity.